Decreased expression of interleukin (IL)-7 receptor α (CD127) on CD8(+) T cells in progressive HIV disease suggests a role for CD127 regulation in HIV immunopathogenesis. The direct effect of HIV on CD127 expression has not been explored to explain these in vivo findings. Peripheral blood mononuclear cells (PBMCs) or isolated CD8(+) T cells from healthy individuals were cultured with either X4 (HIV-1(IIIB)), R5 (HIV-1(BaL)), dual tropic (HIV-1(CS204)), or replication-incompetent (HIV(8E5)) strains of HIV. Both X4 and R5 strains transiently decreased CD127 expression on CD8(+) T cells in PBMC cultures but had no effect on isolated CD8(+) T cell cultures. Isolated CD8(+) T cells exposed to either (1) PBMCs incubated with HIV and cultured in a transwell or (2) supernatants from PBMCs incubated with HIV resulted in decreased CD127 expression. Under no conditions did the replication-incompetent HIV strain affect CD127 expression. As observed in vivo, infection of PBMCs with HIV in vitro results in the downregulation of CD127 surface expression on CD8(+) T cells. Collectively, these data indicate that soluble factor(s) released as a result of HIV infection regulate CD127 expression. Further elucidation of the mechanism(s) of CD127 downregulation will provide important insights into the immunopathogenesis of HIV disease.